CZ94097A3 - Preparation for treating irds and ards - Google Patents

Abstract

Novel compositions for the treatment of IRDS and ARDS contain at least one glucocorticosteroid and a pulmonary surfactant. The duration of treatment with these compositions and the mortality associated with these syndromes can be significantly reduced with the administration of these compositions.

Description

Field of technology

The invention relates to a composition for infant insufficiency (IRDS) for the treatment of adult respiratory syndrome (ARDS).

BACKGROUND OF THE INVENTION

It is known that in the treatment of mothers with glucocorticosteroids (GCS), when these mothers tend to give birth prematurely, their neonates are usually relieved of respiratory insufficiency syndrome (IRDS) as described in H.R. Gamsu, B. M. Mulinger, P. Donai, and C.H. Dash: Antenatal Administration of Bethamethasone to Prevent Respisatory Distress Syndrome in Preterm Infants: Report of a UK Multicenter Trial Brit. J. Obst. Gyn. 1989, 96: 410-10, and in A.N. Papageorgiou and L. Stern: J. Perinat. Copper. 1986, 14: 75-86. Mothers were first given GCS and then efforts were made to delay delivery by at least 24 hours to allow lung tissue to mature by GCS. In addition, premature infants have been administered pulmonary surfactants (LSF) for many years to prevent and / or treat IRDS by the intratracheal or intrabronchial route of A. Jobe and M. Ikegami, Surfactant for the treatment of respiratory distress syndrome, Am. Roar. Respir. Dis. 1987, 136: 1256-75; M.S. Reynolds and K.

A. Wallander, Use of surfactants in the prevention and treatment of neonatal respirators distress syndrome, Clin. Phar. 1989, 8: 559-76. Recently, there have been a number of basic studies using LSFs for the treatment of acute adult respiratory failure (ARDS) and of other origin with good results, for example, this is described in B.B. Lachmann, D. Gommers and E.P. Eijking, Exogenous Surfactant Therapy in Adults, Atemw.-Lungenkrk., 1993, 19: 581-91, T.J. Gregory et al., Survanta supplementation in patients with acute distress syndrome (ARDS) respirators,

Am. J. Respir. Crit. Care Med. 1994, 149: A567. Corticosteroids were administered with little success in the case of ARDS according to G.R. Bernard et al., High-dose conrticosteroids in patiens with adult respiratory distress syndrome, N. Engl. J. Med. 1987, 317: 1565-70.

It has now unexpectedly been found that when a combination of glucocorticosteroids and pulmonary surfactants is administered, a synergistic effect can be achieved in the treatment of both IRDS and ARDS.

SUMMARY OF THE INVENTION

The present invention provides a composition for the treatment of IRDS and ARDS comprising at least one glucocorticosteroid and at least one pulmonary surfactant.

Among the glucocorticoids are those suitable for pulmonary administration, such as betamethasone, Budesonide, methylprednisolone, dexamerhasone and Ciclesonide.

As used herein, the term pulmonary surfactant refers to a number of known substances having the function of natural lung surfactants. These are, in particular, phospholipid-containing compositions which may additionally contain proteins having a similar effect. Of the commercially available products, Curosufroe (Serono, Pharma GmbH, 85716, UnterschleiBheim), a highly pure natural surfactant from homogenised pig lung, Survantaoe (Abbott, GmbH, Wiesbaden), and Alveofactoe (Dr. Karl. Thomae GnmH, Biberach), both of which are bovine lung extracts, and Exosurfoe (Deutsche Wellcome GmbH, Burgwedel), a synthetic phospholipid with excipients, may also be used. Naturally occurring substances such as lung lavage or amniotic fluid extracts, also obtained by genetic engineering, can also be used as proteins with similar activity to surfactants. These include, for example, the proteins designated SP-B and SP-C and their modified derivatives. The amino acid sequence of these proteins, their isolation and their production by genetic engineering is known from WO-86 / 03408, EP-A-251449, WO-89 / 04326, WO-87 / 06943, WO-88 / 03170, EP-A-368823 and EP-A-348967. EP-B-10000O, EP-A-110498, EP-B-119056, EP-B-145005 and EP-B-286O11 disclose non-wettable or non-wettable phospholipid-containing compositions, such compositions. are also useful in the manufacture of the composition of the invention.

The compositions of the invention may be used in powder form for administration by inhalation or in liquid form for administration to the trachea or bronchi. The powder form can be obtained by lyophilizing the liquid surfactant composition, optionally after adding the glucocorticoid, and then micronizing. The compositions according to the invention contain 1-30% by weight of glucocorticoid according to its activity, a table showing the relative activity of these compounds is given, for example, in Goodman / Gillman, Pharmacological Basis of Therapeutics, Pergamon Press, page 1447, 8th edition. up to 95% by weight of the pulmonary surfactant based on dry weight, a typical composition, for example, comprises 7% betamethasone and 92% LSF or 37% methylprednisolone and 63% LSF.

The compositions of the invention are administered 3 to 4 times daily for two to four days. For example, once every six hours by inhalation, a composition containing 4 mg of betamethasone and 50 mg of phospholipid may be administered, or administered to the trachea or bronchi.

Pharmacology

Adult Sprague Dawley rats were given pure oxygen at positive PEEP respiratory pressure to achieve rat oxygenation and then rinsed until their own pulmonary surfactant was washed out, as described by B. Lachmann, B. Robertson and J. Vogel: In vivo lung-lavage as an experimental model of respiratory distress syndrome, Acta Anesth, Scand, 1980, 24: 231-6, D. Háfner, U. Kilian and R. Beume: Comparison of four lung surfactant preparations in an adult model of adult respiratory distress syndrome (ARDS), Am. Roar. Respir. Dis. 1993, 147: A 719 and D. Hafner, PG Germann, D. Hauschke, Pulmonary Pharmacology, 1994, 7, 319-322. This procedure results in the preliminary values of arterial oxygen partial pressure (PaO2) dropping in experimental animals. from 500 to 550 mm Hg for PEEP to 50 to 100 mm Hg. In control animals not treated with LSF, these values remain low throughout the observation period. Five minutes after the oxygen pressure has dropped to the indicated values, LSF is administered, optionally together with the glucocorticosteroid, into the trachea. The circulating gas content is then determined after 5, 30, 50, 90 and 120 minutes. Then the PEEP is reduced from 8 to 6 cm of water column (first PEEP reduction). After a further 15 minutes, PEEP is reduced to 3 cm water column (second PEEP reduction). The blood gas content is determined 5 minutes after each reduction.

In Table 1 the mean values (- standard deviation) of PaO 2 in mm Hg over 5 to 120 minutes (constant PEEP of 8 cm of water) are given in row A following the administration of the wetting agent to the trachea. In line B, the mean values (± standard deviation) of PaO 2 are shown after the first PEEP reduction and after administration of the wetting agent to the trachea. In line C, mean PaO 2 values (± standard deviation) are shown after the second PEEP reduction. The table shows that glucocorticosteroid administration alone, in this case budesonide, had no effect on the PaO2 value. Untreated animals were used as controls. Administration of LSF at 25 or 100 mg / kg resulted in an increase in PaO2. In addition, when 500 µm of budesonide was administered, there was a further substantial improvement in PaO 2 compared to the case where only a wetting agent was administered. Thus, it is apparent that co-administration of glucocorticosteroid and LSF surfactants results in an unexpected effect that is greater than the sum of the effects of the individual agents. In this way, it is possible to save part of the very expensive surfactants or to achieve a higher effect.

Histological observations of the lung tissue of these animals after the experiments have shown strong formation of the so-called hyaline membrane of HM and so-called inflammatory cells, for example neutrophil leukocytes with polymorphic nuclei,

PMNL as an expression of acute respiratory failure.

Experiments conducted with the compositions of the present invention containing dexamethasone or ciclesonide and a mixture of phospholipids in the presence or absence of a wetting protein in this model have shown that both the oxygen supply and the histological changes, particularly HM and PMNL formation have improved significantly. animals treated with LSF or GCS only.

Obviously, there is an unexpected synergistic effect that can be used to treat both IRDS and ARDS and reduce the high mortality in these diseases.

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Claims (7)

PATENT CLAIMS Composition for the treatment of IRDS and ARDS, characterized in that it comprises at least one glucocorticosteroid and at least one pulmonary surfactant. Composition according to claim 1, characterized in that the glucocorticosteroid is betamethasone, budesonide, methylprednisolone, dexamethasone and / or ciclesonide. 3. A composition according to claim 1 wherein the pulmonary surfactant is a mixture of phospholipids. 4. A composition according to claim 3 comprising phospholipids found in natural pulmonary surfactants. 5. A composition according to claim 3, further comprising lung surfactant proteins. 6. A composition according to claim 5 comprising SP-B and / or SP-C proteins and / or modified derivatives thereof. 7. A composition according to claim 4 comprising pulmonary surfactants obtained by lung irrigation.